Gel useful for the delivery of ophthalmic drugs

ABSTRACT

The present invention relates to a solid powder composed of a mixture of a natural or a synthetic polymer which forms a gel, a buffer, such as an hydroxyacid or a dicarboxyacid, a saccharide, one or more drugs useful for the treatment of diseases of the eyes and optionally one or more excipients and/or regulators of the osmotic pressure ophthalmologically acceptable.

This application is a divisional application of U.S. Ser. No. 12/517,445filed on Jun. 16, 2009, which is a 371 of PCT/EP2007/062929 filed onNov. 28, 2007, which claims priority to and the benefit of EuropeanPatent Application No. 06126981.7 filed on Dec. 22, 2006, the contentsof each of which are incorporated herein by reference in their entirety.

The present invention relates to a physiological supplement ormedicament in the form of a solid powder which comprises a mixture of: apolymer which forms a gel, a buffer; a saccharide and one or more activeingredients useful for treating diseases of the eyes, in which saidpowder once is reconstituted with a suitable amount of water, or aliquid solution, provides a gel useful for the prevention or treatmentof the eyes.

Non limiting examples of diseases of the eye are cystinosys, dry eyesyndrome, corneal oedema and diseases of the eyes due to ultravioletradiation.

Cystinosys is a genetic metabolic disease that causes an amino acid,cystine, to accumulate in various organs of the body. Cystine crystalsaccumulate in the kidneys, eyes, liver, muscles, pancreas, brain andwhite blood cells. Without specific treatment, children with cystinosysdevelop end stage kidney failure at approximately age nine.

Cystinosis also causes complications in other organs of the body. Thecomplications include muscle wasting, difficulty swallowing, diabetes,and hypothyroidism. It is estimated that at least 2,000 individualsworldwide have cystinosys, thought exact numbers are difficult to obtainbecause the disease is often undiagnosed and/or misdiagnosed.

The damage to the kidneys and other organs is thought to be due toaccumulation of cystine inside the cells of various body tissues. Thischemical also accumulates in the cornea and iris. After 10 to 20 years,the corneas of some patients become so packed with crystals that thesurfaces may become irregular, occasionally causing small, painfulbreaks.

Treatment with cysteamine eye drops dissolves corneal cystine crystalsand prevents damages of the eyes (N. Eng. J. Med. 347, 111-121; 2002).

Frequent instillation of concentrated solutions of cysteamine isnecessary in order to achieve the desired therapeutic effects.

Dry eye syndrome is characterised by a quantitative (hypolacrimation)and/or qualitative (dyslacrimation) impairment of the tear film ofmultifactorial origin which may or may not cause clinically significantdamage to the eye surface. The prevalence of dry eye syndrome rangesfrom 10 to 40% in the adult population and there is a highly significantcorrelation with age.

Oedema or swelling of the cornea occurs when the cornea is unable tokeep itself clear and fluid begins to accumulate within it. The insidelining of the cornea is responsible of keeping it clear, and if thislayer is damaged symptoms of corneal oedema may occur.

Causes of corneal oedema include disorders of the inside layer of thecornea such as Fuchs' endothelial dystrophy; eye surgery, such ascataract surgery; eye trauma; acute glaucoma with very high eyepressure; contact lens; infections.

Treatment of corneal oedema depends on its cause. Mild oedema can betreated with hypertonic eye drops and ointments. This draws fluid out ofthe cornea and into the tears, and helps to clear the cornea. Moresevere oedema, especially with blister (bullae) formation, may requirecorneal transplant to correct.

Ultra-violet radiation has long been recognized as a factor in thedevelopment of cutaneous cancer, aging of the skin, and mutagenicchanges, it is only within the last decade or less that ultra-violetradiation has been universally recognized as a causative factor inocular pathogenesis.

In humans, the eye has evolved into a sophisticated organ havingneurophysiologic responses to photons in a certain portion of theelectromagnetic spectrum that provides a constant detailed map of theimmediate environment. The action spectrum for these responses lieprimarily within the 400-700 NM wavelength range, which has been labeledthe visible spectrum or “Light”.

Because solar UV radiation is present during most of the daylight hours,the eye may be exposed daily to some amount of solar ultravioletradiation throughout life.

Diseases of the eye due to ultraviolet radiation include age relatedcataract; pterygium; Macular Degeneration such as age relatedmaculopathy (ARM), non age related maculopathy (nARM), age relatedmacular degeneration (AMD); attinic photokeratitis and conjunctivitis.

Most of the conventional ophthalmic drug delivery systems encountergreat problems due to unique physiological conditions of the eye, i.e.,when a conventional liquid ophthalmic formulation is applied to the eye,upon instillation, it is immediately eliminated from the pre cornealarea of the eye because of lacrimal secretion and nasolacrimal drainage.As a result, only 1-10% of the ophthalmic drugs can be utilized bypatients and a frequent instillation of concentrated solutions isnecessary in order to achieve the desired therapeutic effects.

A drug to be applied topically on the eye is more effective if said drugremains in the eye in a time sufficient to exert its preventive orcurative function. To lengthen the retention time of instilledophthalmic drug in the eye and to enhance the bioavailability of theophthalmic drug, various ophthalmic vehicles have been developed.Examples of such ophthalmic vehicles include various inserts, ointments,suspensions and gels. The ophthalmic vehicles known in the art have somedrawbacks. For example, the use of ointments often causes blurredvision. Also, insert is not particularly popular among patients due toits low patient compliance.

Previous uses of gel for ophthalmic use are already known.

Gurny et al, J. Contr. Release (1985), 2:353-361, discloses an oculardrug delivery system which includes cellulose acetophthalate (CAP) latexand Carbopol solution.

Rozier et al., Int. J. Pharm. (1989), 57: 163-168, discloses anion-activated gelling vehicle with a trademark of Gelrite®. However,Rozier et al.'s gelling vehicle has the disadvantages of being convertedinto gel in the presence of mono- or divalent cations.

Joshi et al.'s U.S. Pat. No. 5,252,318 discloses reversibly gellingaqueous compositions which contain at least one pH-sensitive reversiblygelling polymer (such as carboxy vinyl linear or branched orcross-linked polymers of the monomers) and at least onetemperature-sensitive reversibly gelling polymer (such asalkylcellulose, hydroxyalkyl cellulose, block copolymers ofpolyoxyethylene and polyoxypropylene, and tetrafunctional block polymersof polyoxyethylene and polyoxypropylene and ethylenediamine). Joshi etal.'s compositions exhibit significant changes in viscosity in responseto substantially simultaneous changes in both temperature and pH.

Kumar et al., J. Ocular Pharmacol. (1994), 10: 47-56, discloses anocular drug delivery system based on a combination of Carbopol andmethylcellulose. The sol-gel transition of the combination occursprimarily due to an increase in pH because of the presence of Carbopol.Kumar et al., J. Pharm. Sci. (1995), 84: 344-348 (1995), discloses yetanother ocular drug delivery system containing Carbopol andhydroxypropylmethylcellulose. In both systems, a viscosity-enhancingpolymer is added to achieve a reduction in Carbopol concentrationwithout compromising the in situ gelling properties as well as overallrheological behaviors.

Finkenaur et al.'s U.S. Pat. No. 5,427,778 discloses gel formulationscontaining a polypeptide growth factor and a water soluble,pharmaceutically or ophthalmically compatible polymeric material forproviding viscosity within various ranges determined by the applicationof the gel. Both Carbopol gels and Pluronic gels, respectively, aredisclosed in the patent. Pluronic is the trademark for BASF'spolyoxyethylene-polyoxypropylene block copolymers.

Viegas et al.'s U.S. Pat. No. 5,593,683 discloses a method for makingthermo reversible gels for drug or diagnostic agent delivery. The gelscontain a pharmaceutical agent, a surfactant, and a polyalkylenepolyether. The combined total amount of the surfactant and thepolyalkylene polyether does not exceed about 10% by weight.

In the ophthalmologic field there is still a perceived need to have newvehicles useful for preparing medicaments for treating diseases of theeyes, not endowed with the drawbacks of the products known in the art.

It has now been found that a solid powder which comprises a mixture of anatural or synthetic polymer which forms a gel, a buffer, a saccharide,and a drug useful for the treatment of diseases of the eyes, in whichsaid powder, once is reconstituted with a solution provides a gelsuitable for ophthalmic administration.

The powder according to the present invention, respect to the gelpresent on the market presents the following advantages:

-   -   (a) is useful for preparing composition for the delivery of        ophthalmic drugs which are not stable in solution;    -   (b) may not contain irritant preservatives.

In fact, it is well known that the eye drops and the gel for ophthalmicuse present on the market contain preservative to avoid microbialcontamination and said preservatives are irritant for the eyes (J. Am.Coli. Toxicol 8, 589-625; 1989).

The gel according to the present invention remains adherent to the eye,lengthens the retention time of instilled ophthalmic drug in the eye,and enhances the bioavailability of said ophthalmic drug.

It is therefore an object of the present invention a solid powder whichcomprises a mixture of:

-   -   a) a natural or synthetic polymers which forms a gel, an example        of said polymer is a carboxy vinyl polymer such as Carbopol;    -   b) a buffer, such as an hydroxyacid or a dicarboxylic acid        selected from the group comprising phosphate, boric acetate,        citrate, lactate, tartrate, maleate, succinate or fumarate;    -   c) a saccharide, selected from the group comprising glucose,        fructose, mannitol, sorbitol, lactose, trehalose or maltose; and        optionally    -   d) one or more drugs useful for the treatment of diseases of the        eyes.

The powder according to the present invention once reconstituted withwater or a solution, provides a gel suitable for ophthalmic use.

It is a further object of the present invention a gel, useful forpreparing a medicament for the treatment of diseases of the eyes, whichcomprises a mixture of:

-   -   a) a natural or synthetic polymers which forms a gel, an example        of said polymer is a carboxy vinyl polymer such as Carbopol;    -   b) a buffer, such as an hydroxyacid or a dicarboxylic acid        selected from the group comprising phosphate, boric acetate,        citrate, lactate, tartrate, maleate, succinate or fumarate;    -   c) a saccharide, selected from the group comprising glucose,        fructose, mannitol, sorbitol, lactose, trehalose or maltose; and    -   d) one or more drugs useful for the treatment of diseases of the        eyes. A non limiting example of said drugs is: cysteamine;        pilocarpine; epinephrine; tetracycline; phenylephrine; eserine;        timolo; L-carnitine and/or an alkanoyl L-carnitine selected from        the group comprising: acetyl, propionyl, valeryl, isovaleryl,        butyryl and isobutyryl L-carnitine, or an opthalmologically salt        thereof; phosphotine iodide; demecarium bromide; cyclopentolate;        homatropine; scopolamine; chlortetracycline; bacitracin;        neomycin; polymixin; gramicidin; oxytetracycline;        chloramphenicol; gentamycin; penicillin; erythromycin;        carbachol; sulfacetamide; polymixin B′, idoxuridine;        isoflorophate; fluoromethalone; dexamethasone; hydrocortisone;        hydrocortisone acetate; 21-phosphate; fluorocinolone; medrysone;        prednisolone; methyl prednisolone; prednisolone 21-phosphate;        prednisolone acetate; betamethasone; triamcinolone; enzymes;        vitamins; minerals; 3-Hydroxykynurenine O-˜-DL-glucoside or a        derivative thereof, citicholine; taurine; resveratrol, sodium        jaluronate; or mixture thereof.

Preferred active ingredients are those which are not stable in water orin solution.

It is a further object of the present invention a method of preparationof the powder of the invention which comprises the following steps:

-   -   a) preparation of the gel dissolving in water the gelling agent,        a buffer, a saccharide, and optionally one or more drugs useful        for treating diseases of the eye;    -   b) the gel so obtained is divided in single doses and put into        vials;    -   c) to obtain a powder the vials of step b) are lyophilized;        alternatively the gel of point a) is directly subjected to        Spray-drying procedure and the powder so obtained is put, in a        suitable amount, into vials.

The powder so obtained before the use needs to be reconstituted withwater or a solution.

It is a further object of the present invention a physiologicalsupplement or medicament for ophthalmic use, which comprises the powderor the gel of the invention and one or more drugs useful for thetreatment of diseases of the eyes; and optionally one or more excipientsand/or regulators of the osmotic pressure ophthalmologically acceptable.

It is a further object of the present invention a physiologicalsupplement or medicament for ophthalmic use, which comprises the powderor the gel of the invention and as a drug (as active ingredient)cysteamine.

It is a further object of the present invention a physiologicalsupplement or medicament for ophthalmic use, which comprises the powderor the gel of the invention and the following components:

-   -   L-carnitine, or an ophthalmically acceptable salt thereof, 10 at        a dose of 0.1-10%, a preferred dose is 1%;    -   taurine at a dose of 0.1-4%, a preferred dose is 0.5%;    -   sodium hyaluronate at a dose of 0.05-1.5%, a preferred dose is        0.2%;    -   vitamin E at a dose of 0.05-1.0%, a preferred dose is 0.2%;    -   manganese at a dose of 0.01-0.1 mg/L, a preferred dose is 0.051        mg/L;    -   zinc at a dose of 0.5-1.5 mg/L, a preferred dose is 1.02 mg/L;    -   sodium at dose of 5-5000 mg/L, a preferred dose is 30 mg/L;    -   potassium at a dose of 1-1000 mg/L, a preferred dose is 9 mg/L.

This physiological supplement or medicament is particularly useful forthe treatment of dry eye syndrome.

It is a further object of the present invention a physiologicalsupplement or medicament for ophthalmic use, which comprises the powderor the gel of the invention and the following components;

-   -   L-carnitine, or an ophthalmically acceptable salt thereof, at a        dose of 5-15%; preferred dose is 10%;

taurine at a dose of 0.5-4%, a preferred dose is 2%;

sodium hyaluronate at a dose of 0.05-1.5%, a preferred dose is 0.2%;

vitamin E at a dose of 0.05-1.0%, a preferred dose is 0.2%;

-   -   manganese at a dose of 0.01-0.1 mg/L, a preferred dose is 0.051        mg/L;    -   zinc at a dose of 0.5-1.5 mg/L, a preferred dose is 1.02 mg/L;    -   sodium at dose of 5-5000 mg/L, a preferred dose is 30 mg/L;

potassium at a dose of 1-1000 mg/L, a preferred dose is 9 mg/L.

This physiological supplement or medicament is particularly useful forthe treatment of corneal oedema.

It is a further object of the present invention a physiologicalsupplement or medicament for ophthalmic use, which comprises the powderor the gel of the invention and the following components;

-   -   L-carnitine, or an ophthalmically acceptable salt thereof, at a        dose of 1-10%, a preferred dose is 5%;    -   3-Hydroxykynurenine O_(—)3-DL-glucoside 0.01-1 mg/mL, a        preferred dose is 0.1 mg/mL;    -   Taurine at a dose of 0.5-4%, a preferred dose is 2%;    -   Resveratrol at a dose of 0.05-3 mg/mL, a preferred dose is 0.3        mg/mL;    -   Sodium jaluronate at a dose of 0.05-1.5%, a preferred dose is        0.2%;

Vitamin E at a dose of 0.05-1%, a preferred dose is 0.2%;

zinc at a dose of 0.5-1.5 mg/L, a preferred dose is 1.02 mg/L;

manganese at a dose of 0.01-0.1 mg/L, a preferred dose is 0.051 mg/L;

sodium at a dose of 5-5000 mg/L, a preferred dose is 30 mg/L;

potassium at a dose of 1-1000 mg/L, a preferred dose is 9 mg/L.

It is a further object of the present invention a physiologicalsupplement or medicament for ophthalmic use, which comprises

the powder or the gel of the invention and the following components:

-   -   acetyl L-carnitine, or an ophthalmically acceptable salt        thereof, at a dose of 5-30%, a preferred dose is 20%;    -   3-Hydroxykynurenine 0-3-DL-glucoside at a dose of 0.01-1 mg/mL,        a preferred dose is 0.1 mg/mL;    -   Vitamin E at a dose of 0.1-5%, a preferred dose is 1%;    -   Vitamin A at a dose of 15000-35000 Ul, a preferred dose is 25000        UI.

This physiological supplement or medicament is particularly useful forthe treatment of eye diseases due to ultraviolet radiation.

The physiological supplements or medicaments of the invention mayfurther comprise one or more of the following active ingredients:antioxidants, vitamins, Borage oil;

-   -   epithelialising and anti-angiogenic agents; citicholine,        humidifying agents; inorganic elements; regulator of the        cellular osmolarity; antibiotics; antiviral and antifungal        agents; L-carnitine and/or one or more alkanoyl L-carnitines        selected from the group consisting of acetyl, propionyl,        valeryl, isovaleryl, butyryl and isobutyryl L-carnitine, or a        pharmaceutically acceptable salt thereof.

The powder or the gel of the invention, when combined with one or moreophthalmic drugs, is useful for preparing a medicament for the treatmentof diseases of the eye.

Further object of the present invention is a kit comprising the powderof the invention in admixture with one or more active ingredients(useful in the ophthalmic field) and, separately, in the same or in adifferent container/vial, water or a liquid solution suitable forobtaining the gel of the invention.

Further object of the present invention is a kit comprising:

-   -   a) the powder of the invention (not mixed with a drug useful for        ophthalmic use);    -   b) one or more active ingredient useful for ophthalmic use (in        liquid, solid, cream, gel or powder form); and    -   c) water or a liquid solution suitable for obtaining the gel of        the invention; in which the (three) ingredients are into the        same container/vial in separate space, and said (three)        components can be easily mixed together to obtain the gel of the        invention which may be directly administered on the eye.

The expert in container for ophthalmic use can easily suggest suitablecontainers which contains, for example, the gel mixed with one or moredrugs; or a powder and separately (in the same container) a liquid; or 2different powders and a liquid; for single or multiple applications.Different containers/vials are also included in the present invention.

What is meant by pharmaceutically acceptable salt of L-carnitine oralkanoyl L-carnitine is any salt with an acid that does not give rise totoxic or side effects.

These acids are well known to pharmacologists and to experts inpharmacy. Non-limiting examples of such salts are: chloride, bromide,orotate, aspartate, acid aspartate, acid citrate, magnesium citrate,phosphate, acid phosphate, fumarate and acid fumarate, magnesiumfumarate, lactate, maleate and acid maleate, oxalate, acid oxalate,pamoate, acid pamoate, sulphate, acid sulphate, glucose phosphate,tartrate and acid tartrate, glycerophosphate, mucate, magnesiumtartrate, 2-amino-ethanesulphonate, methanesulphonate, choline tartrate,trichloroacetate, and trifluoroacetate.

What is meant by pharmaceutically acceptable salt of L-carnitine oralkanoyl L-carnitine is also a salt approved by the FDA and listed inthe publication Int. J. of Pharm. 33 (1986), 201-15 217, which isincorporated herein by way of a reference.

DISCUSSION OF THE DRAWINGS

FIG. 1 shows shear stress and viscosity vs shear rates of the gelprepared in EXAMPLE 1. The gel resisted the initial rotary motion and asudden increase in shear stress was observed at higher shear rate. Thegel began to flow after shear stress reached its yield point. Thissystem is a Newtonian flow of the pseudoplastic type with no hysteresis.

FIG. 2 shows shear stress and viscosity vs shear rates of the gelprepared in EXAMPLE 2. The gel resisted the initial rotary motion and asudden increase in shear stress was observed at higher shear rate. Thegel began to flow after shear stress reached its yield point. Thissystem is a Newtonian flow of the pseudoplastic type with no hysteresis.

FIG. 3 shows shear stress and viscosity vs shear rates of the gelprepared in EXAMPLE 3. It can be observed with this gel that shearstress increases linearly with an increase in shear rate. Thisgelatinous system presents typical non-Newtonian flow behavior.

FIG. 4 shows shear stress and viscosity vs shear rates of the gelprepared in EXAMPLE 4. The gel resisted the initial rotary motion and asudden increase in shear stress was observed at higher shear rate. Thegel began to flow after shear stress reached its yield point. Thissystem is a Newtonian flow of the pseudoplastic type with no hysteresis.

FIG. 5 shows the cumulative amount of cysteamine released vs timeprofiles for gel prepared as in EXAMPLE 1. The drug released about 42%into the medium after 30 min and then in gradual fashion. Approximately96% of the cysteamine was released from the gel after 6 h.

FIG. 6 shows the cumulative amount of cysteamine released vs timeprofiles for gel prepared as in EXAMPLE 2. The drug released about 46%into the medium after 30 min and then in gradual fashion. Approximately98% of the cysteamine was released from the gel after 6 h.

The following examples are illustrative, but not limiting the scope ofthe present invention. Reasonable variations, such as those occur toreasonable artisan, can be made herein without departing from the scopeof the present invention.

Materials

Carbopol 974P NF (Noveon), cysteamine and all other chemicals, includingtartaric acid and benzalconium chloride, were purchased from Sigma andwere used as received.

EXAMPLE 1

3 g of Carbopol 974P NF (Noveon) were slowly added to 190 mL of watercontaining 20 mg of benzal conium chloride, the solution was kept understirring at room temperature for 18 h. Then, 500 mg of L-tartaric acid,followed by 6 g of mannitol and finally 1 g of cysteamine were added,keeping the solution under stirring until the cysteamine was completelysolubilized.

The gelatinous system thus obtained was divided into fractions of 3 mLin 10-mL vials. Said vials were lyophilized for 24 h and a white solidwas obtained.

Adding 3 mL of water to the lyophilized vial a gelatinous system havingthe following characteristics was readily obtained:

-   -   pH=4.0-4.3;    -   Osmotic pressure=229 mOsm/kg.

EXAMPLE 2

10 mg of benzalconium chloride and 500 mg of L-tartaric acid were addedto 95 g of a 1.5% Carbopol 974P NF aqueous solution. A very fluidopalescent solution was obtained. To the opalescent solution were added3 g of sorbitol and 1 g of cysteamine. The mixture so obtained was keptunder stirring until the cysteamine was completely solubilized.

The gelatinous system thus obtained was divided into fractions of 3 mLin 10-mL vials. Said vials were lyophilized for 24 h and a white solidwas obtained.

Adding 3 mL of water to the lyophilized vial a gelatinous system havingthe following characteristics was readily obtained:

-   -   Osmotic pressure=267 mOsm/kg;    -   pH=4.5-5.0.

EXAMPLE 3

1 g of L-tartaric acid was added to 95 g of a 1.5% Carbopol 974P NFaqueous solution, a very fluid opalescent solution was obtained. To thissolution 3 g of sorbitol and 1 g of cysteamine were added, the mixtureso obtained was kept under stirring until the cysteamine was completelysolubilized.

The gelatinous system thus obtained was divided into fractions of 3 mLin 10-mL vials. Said vials were lyophilized for 24 h and a white solidwas obtained.

Adding 3 mL of water to the lyophilized vial a gelatinous system havingthe following characteristics was readily obtained:

-   -   pH=4.0-4.3    -   Osmotic pressure=297 mOsm/kg.

EXAMPLE 4

In 400 mL of water 3 g of Carbopol 974P NF, 2 g of tartaric 25 acid, 6 gof lactose and finally 2 g of cysteamine in the sequence above reported,at room temperature, were dissolved. The slightly viscous solution,constantly kept under stirring was concentrated through a Spray-drying(Buchi B-191) under the following conditions: Inlet=60° C., ASP=82,Pump=0.06.

A white solid was obtained.

Adding 200 mL of water, to the white solid, a gelatinous system havingthe following characteristics was readily obtained:

-   -   pH=4.0-4.3    -   Osmotic pressure=225 mOsm/kg.

Reological Studies

The reo logical studies were carried out with a rotational viscometer ofthe concentric cylinder type (Viscometer TV-10 Toky Sangyo equipped witha small sample adapter and rotor type M3). The viscosity and shearstress of the samples were measured at various rates at 25° C. Thetemperature was maintained within +/0.1° C. by a recirculating bathconnected to the viscometer. The samples were equilibrated for fiveminutes to reach the running temperature prior to each measurement.

In Vitro Release Studies

In vitro release experiments were carried out with a dissolutioninstrument (Sotax AT 7 smart) equipped with a cell cream. Approximately2 g of gel containing cysteamine prepared as reported in EXAMPLES 1 and2 were weighed in the cell cream and placed in a 1000-mL vesselcontaining 500 mL of 50 mM acetate buffer, 25 pH=4.5. The experimentswere carried out at 37° C. and with a 50 rpm stirring paddle. At regularintervals, 1 mL of solution was withdrawn from the vessel and filteredusing a 0.2 micron filter (Millez-FG Millipore) analyzed by HPLC todetermine cysteamine concentration.

The HPLC chromatographic system composed of a pump (Waters 600); andautosampler (Waters 717); a UV detector (Waters 486) and integrator(Waters Empower 2). An inverse phase silica column (ODS-3 4.6×250 mm 5micron) was used for the drug separation, pH=3, and as mobile phase wasused a sodium dihydrogen phosphate buffer system. The flow rate and UVwavelength were 0.8 mL/min and 205 nm, respectively. The drugconcentrations were determined by measuring the peak area in comparisonwith the peak area of known standards.

Carbopol® is a registered trademark of Noveon, Inc. (formerly B.F.Goodrich Co.) for a family of polymers that are used as thickeners,suspending agents and stabilizers.

L-carnitine and its alkanoyl derivatives are known compounds, thereparation process for which is described in U.S. Pat. No. 4,254,053.

3-Hydroxykynurenine 0-3-DL-glucoside is a product sold by Sigma-Aldrich,catalogue 2006; product code n° H 1771.

The physiological supplement or medicament according to the presentinvention may be bought with or without medical prescription.

The physiological supplements or medicaments according to the presentinvention are composed of active ingredients which are familiar tooperators in the medical field and already in use in clinical practice,and their pharmacotoxicological profiles are known.

Their procurement therefore is very easy, inasmuch as these are productswhich have been on the market now for a long time and are of a gradesuitable for human or animal administration.

In the following are reported non limiting examples of compositionaccording to the present invention.

Formulation 1

The powder or the gel of the invention and cysteamine. Thisphysiological supplement or medicament is particularly useful for thetreatment of cystinosis.

Formulation 2

The powder or the gel of the invention and the following components(active ingredients):

-   -   L-carnitine 1%;    -   Taurine 0.5%;    -   sodium hyaluronate 0.2%;    -   vitamin E 0.2%;    -   manganese 0.051 mg/L;    -   zinc 1.02 mg/L;    -   sodium 30 mg/L;    -   potassium 9 mg/L;    -   Osmolality of about 125 mOsmols/kg.

This physiological supplement or medicament is particularly useful forthe treatment of dry eye syndrome.

Formulation 3

The powder or the gel of the invention and the following components:

-   -   L-carnitine 10%    -   taurine 2%    -   sodium jaluronate 0.2%    -   vitamin E 0.2%    -   zinc 1.02 mg/L    -   manganese 0.051 mg/L    -   sodium 30 mg/L    -   potassium 9 mg/L    -   Osmolality of about 1200 mOsmols/kg.

This physiological supplement or medicament is particularly useful forthe treatment of corneal oedema.

Formulation 4

The powder or the gel of the invention and the following components:

-   -   L-carnitine 5%    -   3-HydroXYkYnurenine O-P-DL-glucoside 0.1 mg/mL    -   Taurine 2%    -   Resveratrol 0.3 mg/mL    -   Sodium jaluronate 0.2%    -   Vitamin E 0.2%    -   Zinc 1.02 mg/L    -   Manganese 0.051 mg/L    -   sodium 30 mg/L    -   5 potassium 9 mg/L.

This physiological supplement or medicament is particularly useful forthe treatment of eye diseases due to ultraviolet radiation.

Formulation 5

The powder or the gel of the invention and the following components:

-   -   Acetyl L-carnitine 20%    -   3-Hydroxykynurenine O-β-DL-glucoside 0.1 mg/ml    -   Vitamin E 1%    -   Vitamin A 25000 UI.

This physiological supplement or medicament is particularly useful forthe treatment of eye diseases due to ultraviolet radiation.

1. A solid powder comprising: a carboxy vinyl polymer; a buffer; asaccharide; and L-carnitine and/or one or more alkanoyl L-carnitine,said solid powder providing a gel suitable for ophthalmic use whenreconstituted in water.
 2. The solid powder of claim 1, wherein thecarboxy vinyl polymer is carbopol.
 3. The solid powder of claim 1,wherein the buffer is a hydroxyacid or a dicarboxylic acid selected fromthe group consisting of phosphate, boric acetate, citrate, lactate,tartrate, maleate, succinate and fumarate buffer.
 4. The solid powder ofclaim 1, wherein the saccharide is selected from the group consisting ofglucose, fructose, mannitol, sorbitol, lactose, trehalose and maltose.5. The solid powder of claim 1, further comprising an excipient, adiluent or a regulator of the osmotic pressure ophthalmologicallyacceptable.
 6. Physiological supplement comprising the solid powder ofclaim 1 and further comprising: L-carnitine    1%; taurine  0.5%; sodiumhyaluronate  0.2%; vitamin E  0.2%; manganese 0.051%; zinc  1.02%;sodium 30 mg/L; potassium  9 mg/L.


7. Physiological supplement comprising the solid powder of claim 1 andfurther comprising: L-carnitine  10%; taurine   2%; sodium hyaluronate0.2%; vitamin E 0.2%; zinc  1.02 mg/L; manganese 0.051 mg/L; sodium   30mg/L; potassium    9 mg/L.


8. Physiological supplement comprising the solid powder of claim 1 andfurther comprising: L-carnitine   5%; 3-HydroxykynurenineO-P-DL-glucoside  0.1 mg/mL; taurine   2%; resveratrol  0.3 mg/mL;sodium jaluronate 0.2%; vitamin E 0.2%; zinc  1.02 mg/L; manganese 0.051mg/L; sodium   30 mg/L; potassium    9 mg/L.


9. Physiological supplement comprising the solid powder of claim 1 andfurther comprising: acetyl L-carnitine 20%; 3-HydroxykynurenineO-β-DL-glucoside 0.1 mg/mL; vitamin E  1%; vitamin A 25000 UI.


10. Kit comprising the solid powder of claim 1 and water or a liquidsolution.
 11. Kit of claim 10, in which each component is packaged inthe same vial or in two different vials.
 12. Kit comprising: a) thepowder of claim 1, without L-carnitine and/or one or more alkanoylL-carnitine; b) L-carnitine and/or one or more alkanoyl L-carnitine inthe form of liquid, solid, cream, gel or powder; and c) water or aliquid solution.
 13. Kit of claim 12, wherein each component is packagedin a separate form in the same vial or in different vials.